An Idea Factory for Pathology Informatics and the Clinical Laboratory. Presented by the Pathology Education Consortium (PEC).

17 posts from March 2012

In a series of previous notes, I discussed in-office histology labs whereby dermatology, gastroenterology, and urology practices construct a lab on the office premises and begin to prepare their own histology slides (see: Corrected Definition for a Pod Lab and a Look at In-Office Labs; Many Big Urology Practices Now Utilize an In-Office Histology Lab and Their Own Pathologist). These slides are then read by a pathologist who operates under a fee-for-service contract with the group. The office bills globally for the diagnostic service and the pathologist is compensated for his or her services performed in the laboratory. This usually means he or she receives the Medicare professional fee, less the practice expense portion of the professional fee, for a net of about $26 per slide. A pathologist will also receive a modest lab management fee. The clinical groups retains the technical component which is about $70 per slide.

There are approximately 9,000 office-based dermatologists practicing in the U.S. An estimated 15% currently operate full-service histology labs. The major driver for these practices to move in this direction is to increase office revenue to offset other reductions by Medicare and health insurance companies. I learned all of these facts in a recent teleconference sponsored by Laboratory Economics that featured Joe Plandowski (see: Webinar on the "Insourcing" of Pathology Specimens by Clinical Practice Groups). Joe co-founded In-Office Pathology in 2005. Over the past six years, IOP has helped to launch and manage 50 histology labs in 18 states for urology, gastroenterology, and dermatology practices.

Joe clarified one point during the presentation about which I was a little fuzzy -- exactly where the pathologists who staff these in-office labs were coming from. It turns out, at least in Joe's experience, that they are recruited from the local hospital pathology groups. In fact, this source is almost essential for this business model to work because the other members of the pathology group can cover the in-office pathologist when he or she goes on vacation. Interesting enough, Joe has also not experienced any difficulties recruiting histotechs to work for in-office labs despite an apparent shortage of them for hospital labs. Apparently the histotechs prefer the hours, environment, and focused work of these facilities.

If there is a "loser" with regard to this growth of in-office labs, it might be viewed as the hospitals. They capture the technical component (TC) when the histology work is done by them but lose it to the practices operating the in-office labs. So, you may ask, why would hospitals "tolerate" in-office labs in the community? Probably because there's not much they can do to stop the trend and also because they don't want to alienate the private practice physicians. Also keep in mind that, at some time in the future, hospitals may want to purchase these same practices (see: The Increasing Tempo of Physician Practice Purchases by Hospitals). The national surgical pathology reference labs are also aggressively marketing partnerships arrangements under which they manage an in-office pathology lab and perform and bill for professional services. Having local hospital pathologists staffing in-office labs may be perceived by hospital executives as preferable to providing an opportunity for these national reference labs to gain access to town business.

The economics of in-office anatomic pathology laboratories are very straightforward. For every dollar of revenue collected, the practice keeps about 50 cents after paying all the laboratory related expenses, including pathology. A pre-tax margin of 50 percent exists because in-office anatomic pathology laboratories do not carry expenses related to couriers, sales/marketing representatives, or sophisticated software programs. Couriers are not needed because tissue specimens do not leave the practice office. Sales/marketing representatives are not needed because by federal regulations only specimens from patients of the practice can be processed at the in-office anatomic pathology laboratory. Sophisticated software packages are not needed for data entry and results reporting because the in-office pathology laboratory software package is interfaced to the practice’s.

A new study...reveals that the presence of Helicobacter pylori (H. pylori) bacteria is associated with elevated levels of glycosylated hemoglobin (HbA1c), an important biomarker for blood glucose levels and diabetes. The association was even stronger in obese individuals with a higher Body Mass Index (BMI)....There have been several studies evaluating the effect of the presence of H. pylori on diabetes outcomes, but this is the first to examine the effect on HbA1c, an important, objective biomarker for long-term blood sugar levels....“Obesity is an established risk factor for diabetes and it is known that high BMI is associated with elevated HbA1c. Separately, the presence of H. pylori is also associated with elevated HbA1c,” said [one of the study authors] “We hypothesized that having both high BMI and the presence of H. pylori would have a synergistic effect, increasing HbA1c even more than the sum of the individual effect of either risk factor alone. We now know that this is true.” H. pylori lives in the mucous layer lining the stomach where it persists for decades. It is acquired usually before the age of 10, and is transmitted mainly in families....[P]revious studies have confirmed the bacterium’s link to stomach cancer and elucidated genes associated with its virulence, particularly a gene called cagA. Regarding H. pylori‘s association with elevated HbA1c,[the study authors] believe the bacterium may affect the levels of two stomach hormones that help regulate blood glucose, and they suggest that eradicating H. pylori using antibiotics in some older obese individuals could be beneficial. More research will be needed to evaluate the health effects of H. pylori and its eradication among different age groups and in relation to obesity status, the authors noted.

To keep everyone on the same page, here is a brief description of HbA1c (see: Glycated hemoglobin):

In the normal 120-day lifespan of the red blood cell, glucose molecules react with hemoglobin, forming glycosolated hemoglobin. In individuals with poorly controlled diabetes, the quantities of these glycosolated hemoglobins are much higher than in healthy people. Once a hemoglobin molecule is glycosolated, it remains that way. A buildup of glycosolated hemoglobin within the red cell, therefore, reflects the average level of glucose to which the cell has been exposed during its life-cycle. Measuring glycosolated hemoglobin assesses the effectiveness of therapy by monitoring long-term serum glucose regulation. The HbA1c level is proportional to average blood glucose concentration over the previous four weeks to three months.

This is an interesting story about the pathophysiology of the gastric mucosa. Clearly, a chronic infection of the mucosa with H. pylori causes a number of mucosal "systems" to go awry leading to gastric ulcers and adenocarcinoma/lyphoma in a small percentage of patients. Infection also causes an elevation of HbA1c which is even worse in obese patients. We also know that weight loss can ameliorate or cure diabetes. Bariatric surgery can have a similar effect, even prior to any weight loss (see: Bariatric Surgery Cures Adult-Onset Diabetes; Is This a Problem?).The possibility now exists that the bacterium may affect the levels of two stomach hormones that help regulate blood glucose. Hence the elevated HbA1c with infection. I am looking forward to research that might indicate that antibiotic treatment of the infection can cure diabetes as well as gastric ulcers.

Are symptom checklists more for marketing than diagnosis? Are symptom checklists more for marketing than for diagnosis? It began suddenly a little over 10 years ago....The questions [that healthcare consumers began to ask about] drugs did not reflect breaking news or the results of scientific studies. Rather, they were a reflection of sound bites, advertisements and the draw of celebrities who endorsed them, all part of carefully conceived marketing schemes....[I]n 1997, when the Food and Drug Administration loosened its regulations and the United States became one of only four countries to allow direct-to-consumer advertising (the others are New Zealand, Bangladesh and South Korea), we entered a new era in pharmaceutical consumerism.Players in the drug industry began aiming their advertisements at patients, and their goal was to define in the minds of patients not only the beneficial effects of the drugs but also the diseases they were designed to treat.As Vince Parry, a well-known marketing expert, counseled his colleagues, “If you can define a particular condition and its associated symptoms in the minds of physicians and patients, you can also predicate the best treatment for that condition.”The phenomenon is sometimes referred to as “disease mongering,” redefining what is normal and abnormal in a way that widens potential markets for those who sell treatments. And, as detailed in a recent study in the journal Social Science & Medicine, one marketing strategy has accomplished more in this regard than any other by using what has come to be the very symbol of quality and reliability for doctors and patients everywhere: the checklist.Placed on Web sites, on downloadable apps and in pamphlets in doctors’ offices, these checklists of symptoms have become a critical part of every major pharmaceutical marketing campaign. What makes them so attractive is that they make it easy for patients to diagnose their own ailments, to take some control over their own health.What makes the checklists so powerful is their ability to influence patient preferences....“The whole point of tools like this one is to confine people’s experiences into these categories in order to make a diagnosis in line with the branded drug,” said the author of [this recent study about checklists].

The connection between these disease checklists and disease-mongering is interesting. I have addressed this latter topic in previous notes (see: Disease Mongering (i.e., Medicalization) by Pharmaceutical Companies; Medical Device Mongering, a Variant of Disease Mongering). All of this reduces in my mind to the following: the pharmaceutical industry, through its DTC marketing, is expanding the definition of disease in the minds of consumers; this provides incentives for consumers to self-diagnose their own illnesses; these consumers are then persuaded to request treatment of these diseases with the advertised drugs.

An article was recently published in the American Journal of Clinical Pathology entitled "Cases with addenda increased from 0.9% in 1993 to 8.6% in 2008." It describes an interesting facet of anatomic pathology LIS (AP-LIS) reporting in the pathology department at Yale. Here's the abstract:

Addenda are typically used to report results of additional studies that are delayed relative to histopathologic studies. However, the frequency and pattern of use of addenda have not been previously reported. We studied the dynamics of addenda creation within the same month at 5-year intervals during a 15-year period at our institution. The number of addenda and type and impact of information communicated in addenda were assessed in the month of July in 1993, 1998, 2003, and 2008, and the possible role of addenda in quality improvement was evaluated. Cases with addenda increased from 0.9% in 1993 to 8.6% in 2008. In 5.6% of addenda, there was information that might have been better reported in an amendment, suggesting that criteria for amendments need to be universally implemented. Charting trends and types of addenda offered opportunities for quality improvement by identifying weaknesses in the workflow organization of the laboratory.

Reporting a surgical pathology case with an AP-LIS is becoming much more complex than the situation, say, two or three decades ago. To report out a case previously, almost total attention was paid to the H&E slides with an occasional delay for special stains. The goal, as today, was to arrive at a diagnosis as quickly as possible. The tissue-submitting physician and patient were, of course, also eager to receive the report on a timely basis. A tension has always been in play between the desire to issue the report and the need for a delay occasioned by additional tests such as immunohistochemistry (IHC). However, there are many more "ancillary" test results currently that bear on the final report and need to be taken into consideration.

Out of this milieu and partly connected to the growing maturity of AP-LISs, the following vocabulary emerged for surgical pathology reports: an amendment indicates that a significant change to the report and diagnosis is being reported and an addendum indicates that new information is being reported which does not substantively change the diagnosis. I am constructing these definitions out of my head. I am sure that they are codified somewhere in the literature and in vendor documentation. However, I am also sure that there is not a common understanding of the terms across all pathologists and AP-LIS vendors. Hence the statement in the abstract above: criteria for amendments need to be universally implemented. This was in response to the study finding that "in 5.6% of addenda, there was information that might have better been reported in an amendment."

I strongly endorse the development of such criteria. I am not sufficiently familiar with the field of synoptic reporting to discuss whether this field is the most appropriate vehicle for the development of such criteria. Readers who are better informed may want to join into this discussion. A recent editorial about this same topic appeared in Pathology and made reference to two other articles in the journal issue (see: Surgical pathology reporting at the crossroads: beyond synoptic reporting). Below is an excerpt from it that makes some important points:

[A]s we increasingly used clinical information and ancillary studies such as immunohistochemistry, cytogenetics, molecular analyses and flow studies to derive our diagnoses, two issues obfuscated our thinking. Firstly, the method for incorporation of ancillary studies is not clearly defined within this structure, and some pathologists have been reluctant to incorporate results from other laboratories, even when that information provides a critical part of their final conclusion. Secondly, once pathology data are derived from multiple modalities other than simply morphology, the traditional report structure does not make logical provision for a ‘Synthesis’ in which information from multiple modalities, often of varying predictive value, can be combined and weighed inferentially to derive higher elements, often part of the conclusion. Some have used ‘Comment’ or ‘Commentary’ as an additional heading to define this component. Others have developed their synthesis within the ‘Conclusion’ section. This represents a lack of consistency in the use of this section since most pathologists use it as a summary, i.e., a shortened repetition of what is already in the rest of the report, and increasingly it is used as a banner in the first part of a report, rather as a newspaper headline.

A clinical study...shows that a new treatment for psoriasis could be associated with a significant decrease in vascular inflammation, a major risk factor of cardiovascular disease. Psoriasis is a chronic inflammatory disease of the skin and joints that affects up to 3% of the population. This disease is associated with a greater risk of heart attack (infarction) and stroke. The goal of this clinical study was to show that a treatment to reduce skin inflammation in psoriasis patients could be associated with a decrease in vascular inflammation. The study had positive results, as vascular inflammation decreased significantly in patients suffering from psoriasis who were treated with adalimumab, a biological anti-inflammatory compound. The study also showed a 51% decrease in C-reactive protein among patients treated with adalimumab compared to a 2% decrease among patients in the control group. These results are significant, as a high level of C-reactive protein is known to be associated with an increased risk of heart attack and stroke. In relation to the treatment of psoriasis, 70% of patients who received the compound presented with a major decrease in skin lesion severity, compared to 20% of patients in the control group....“[One of the study authors] added that this clinical research study suggests that it is possible to assess the impact of psoriasis treatments on the heart without having to resort to long-term studies that require thousands of patients and have higher costs.

The significance of the last sentence above is that the degree of cardiovascular disease for each of these study patients was measured at both the start and end of the study with positron emission tomography (PET), a type of medical imaging, to scan the carotid arteries and the ascending aorta. These PET studies enabled the assessment of small changes in the arteries, thus avoiding the necessity of longer-term, and thus more expensive, assessment of disease progression.

Here's a brief summary of the autoimmune basis for psoriasis from the Wikipedia:

[One hypothesis for psoriasis] sees the disease as being an immune-mediated disorder in which the excessive reproduction of skin cells is secondary to factors produced by the immune system. T cells (which normally help protect the body against infection) become active, migrate to the dermis and trigger the release of cytokines (tumor necrosis factor-alpha TNFα, in particular) which cause inflammation and the rapid production of skin cells. It is not known what initiates the activation of the T cells. The immune-mediated model of psoriasis has been supported by the observation that immunosuppressant medications can clear psoriasis plaques. However, the role of the immune system is not fully understood....

Laboratory Economics is sponsoring a 60-minute conference call on Wednesday, March 28, 2012, at 2:00 p.m. EST with Joe Plandowski, co-founder of In-Office Pathology, and David Kemler, consultant for the company. Discussion will focus on “why” and “how” dermatology practices are now insourcing histology.

Learn why dermatologists have begun insourcing histology

Review a step-by-step pro forma for a five-derm group

Learn how local pathologists can adapt and benefit from this trend

Point your browser to the Laboratory Economics web site for more details.

...Epocrates officials were [recently] showing off an iPad version of their new electronic health record at the HIMSS12 Conference and Exhibition in Las Vegas....Now comes word that the San Mateo, Calif.-based company is abandoning plans to roll out its certified EHR to focus on its mobile clinical tools for physicians. Company officials announced ...that they’re ending the two-year-old project and plan to either sell the EHR assets or find a business partner....In its Feb. 28 announcement, Epocrates reported a net loss of $3.6 million in 2011, including $6.5 million in the fourth quarter. The company had lost $3.8 million in 2010, but had posted net income of $2.7 million for the last quarter of that year...."Epocrates' success this year will be defined by our ability to realize the full potential of our physician network – more than 340,000 strong,” [the interim president and chief executive officer] concluded. “Our primary focus will be to strengthen our position of trust with physicians, based on value, which in turn will drive enhanced commercialization opportunities for our business." In an interview last week..., Epocrates Chief Medical Information Officer Thomas Gianulli....said the company couldn’t sustain both its EHR business and its core reference tools business without suffering some loss of quality. Gianulli said the EHR product still needed some work to entice buyers looking to qualify for Stage 2 of the federal government’s meaningful use provisions. “It wasn’t feature-complete yet,” he said.

All of this is very interesting. The office EHR market is getting crowded with Practice Fusion as a formidable rival (see: Practice Fusion CEO Calls His Company the Largest EMR Provider). However, this latter company has also been facing some ethical challenges, given the fact that its free version is supported by advertisements and also assumes ownership of the anonymized patient data contained in the records (see: Practice Fusion Supported by Advertising and Owns Anonymized Data). Note the quote from the Epocrates president and CEO above: “Our primary focus will be to strengthen our position of trust with physicians, based on value, which in turn will drive enhanced commercialization opportunities for our business."

Contrast this with the company decision to withdraw from the office EHR market which is highly competitive and also highly regulated by the federal government. Moreover, it's possible that a business model of selling ads for EHRs and anonymized data to the pharmaceutical industry has the risk of later blowback, hurting the physician trust which the company requires for its primary line of business, smartphone physician apps.

The dark art of movie promotion increasingly lives on the Web, where studios are playing a wilier game, using social media and a blizzard of other inexpensive yet effective online techniques to pull off what may be the marketer’s ultimate trick: persuading fans to persuade each other. The art lies in allowing fans to feel as if they are discovering a film, but in truth Hollywood’s new promotional paradigm involves a digital hard sell in which little is left to chance — as becomes apparent in a rare step-by-step tour through the timetable and techniques used by Lionsgate to assure that “The Hunger Games” becomes a box office phenomenon when it opens.... While some studios have halted once-standard marketing steps like newspaper ads, Lionsgate used all the usual old-media tricks — giving away 80,000 posters, securing almost 50 magazine cover stories, advertising on 3,000 billboards and bus shelters. But the campaign’s centerpiece has been a phased, yearlong digital effort built around the content platforms cherished by young audiences: near-constant use of Facebook and Twitter, a YouTube channel, a Tumblr blog, iPhone games and live Yahoo streaming from the premiere.

Everyone in the diagnostic and healthcare industry should take a look at the last sentence above relating to how social media have been the "centerpiece" of the marketing campaign for this new movie. Clinical labs need to think about what information can be posted on their web sites or on Facebook/Twitter that would be of interest to their physician clients or patients. Keep in mind that most healthcare consumers have almost an insatiable appetite for information about lab testing and particularly, among older patients, about cancer and cardiovascular disease surveillance. Lab directors only need to look among younger employees to find enthusiastic advocates for social media. Harness the energy of those with sophisticated writing skills to help market your organization at very low cost.

One of my favorite examples of a dual-use web site that has value for both physicians and patients is that of ARUP that offers a set of lab algorithms for the diagnosis of disease (see: ARUP Offers Lab Algorithms for Disease Diagnosis Support). You can take a look at this useful tool yourself (see: ARUP Consult: The Physician's Guide to Laboratory Test Selection and Interpretation). By dual-use, I mean that the algorithms were obviously developed to assist ARUP's physician clients in selecting the appropriate tests to order from the lab. Nevertheless, they are also available for anyone surfing the web so that I suspect that many healthcare consumers also use them to obtain valuable information about their own heath and diagnostic work-ups.

This is a guest blog by Theo McCormick. He is the Director of RxDx Services, Pharmaceutical & Diagnostics Consulting, Management Science Associates, in Pittsburgh, PA.

For the the readers of this blog, it is established that clinical lab testing has a profound impact on clinical decisions, providing clinicians with information that aids in the prevention, diagnosis, treatment, monitoring and management of diseases. For pharmaceutical organizations, these insights are in the evolutionary infancy as pharmaceutical market researchers...and business intelligence analysts [begin] to understand the dynamics of clinical value, clinical utility, access and reimbursement to build a successful laboratory diagnostics and data strategy that will ensure appropriate uptake of their brand and increase market share. The biopharmaceutical industry is beginning to understanding how the lack of consistent testing in populations needing screening tests, or barriers to access to a specific assay, prevent a clinician from making the best clinical decisions. These issues can decrease appropriate use of a drug and negatively impact a brand.

As the lab industry consolidates and LIS/Billing/EMR systems grow from stand alone single-institution datasets to national interconnected real-time datamarts, the information contained has value beyond the patient - clinician interaction. Pharmaceutical brand teams, health policy makers and payors are becoming increasingly knowledgeable about these large, de-identified laboratory datasets available from various organizations [such as large national reference labs]. HIPAA compliant Anonymous Patient-Level Data (APLD) contains no protected health information. These aggregated results typically include results, payor types, ICD-9 codes and more, all of which can help a brand team optimize targeting criteria and add a new dimension to understanding the market opportunities.

As an example of the power of these aggregated data-sets, we recently examined nearly 3 million HCV Ab assays over 18 months to determine differences in positivity throughout the US. The top 10 cities (as defined by the number of assays) are shown below. Each of these metropolitan areas has at least 1500 physician accounts that contribute to the data. The national HCV Ab positive rate is 6.4%. Baltimore, Maryland stands out as a metropolitan area with higher then average HCV positive rate. ZIP Codes that did not align with any metropolitan area (as defined by US Census Bureau) are noted as 'Rural or No Code' and it is notable that the HCV Ab positive rate for this segment of the population is the nations’ highest (see below). As laboratory datasets merge and become larger, lab professionals may see an increase in the interest in their datasets for external use and analysis by biopharma organizations.

Prompted by a recent post of tumor genetic heterogeneity (see: One Tumor Biopsy May Be Insufficient to Reveal Genetic Landscape), a reader, Gregory D. Pawelski, responed with a comment that was very interesting so I am promoting it to the level of a note. He describes himself as a self-taught cancer patient advocate and student of cancer biology. At the end of the note, he questions the value of genomic testing of tumors. Boldface emphasis mine. --Bruce Friedman

This "intratumor heterogeneity" issue is not a new revelation to cell function assaysts. As you can see, searching for these genetic predispositions, it is like searching for a needle in a haystack. One can chase all the mutations they want, because if you miss just one, it may be the one that gets through. Or you can look for the drugs that are "sensitive" to killing all of your cancer cells, not theoretical candidates.

Contrary to [analyte]-based genomic and proteomic methodologies that yield static measures of gene or protein expression, functional profiling provides a window on the complexity of cellular biology in real-time, gauging tumor cell response to chemotherapies in a laboratory platform. By examining drug induced cell death, functional analyses measure the cumulative result of all of a cell's mechanisms of resistance and response acting in concert. Thus, functional profiling most closely approximates the cancer phenotype.

Testing of one sample of the tumor may well not render an accurate environment, unless you are recognizing the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. The human tumor primary culture microspheroid contains all of these elements. Studying cancer response to drugs within this microenvironment would provide clinically relevant predictions to cancer patients. It is the capacity to study human tumor microenvironments that distinguishes it from other platforms in the field.

[Cancer researchers] have observed some degree of "genetic drift" where [metastases] tend to be somewhat more resistant to drugs than primaries. Over the years, [researchers] have often encouraged physicians to provide nodal, pleural or distant site biopsies to give the "best shot" at the "most defended" of the tumor elements when metastatic disease is found.

The tumor of origin (as in the NEJM study as well) and the associated [metastases] tend to retain consanguinity. That is, the carcinogenic processes that underlie the two populations are related. This is the reason they do not see "mixed responses" (one place in the body getting better and another place in the body getting worse), but instead, generally see response or non-responses.

Heterogeneity likely underlies the recurrences that are seen in almost all patients. This is why they try to re-biopsy and re-evaluate when recurrences are observed. Heterogeneity remains a theoretical issue no matter what platform one uses. Why complicate this fact by using a less biologically relevant method like genomics that only scratches the surface of the tumor biology?